Is it time to move from the Unidimensional RECIST 1.1 Response Assessment Criteria to a Volumetric Evaluation in the Present Era of Image-based Oncology? An Evaluation in Locally Advanced Head Neck Cancers Undergoing Treatment.

AIMS: Tumour response assessments, as per Response Evaluation Criteria in Solid Tumours (RECIST 1.1), are based on the sum of diameters (SODs) of the primary tumour (longest diameter) and/or short axis diameter of lymph nodes. This study evaluates the response categorisation as per RECIST 1.1 vs Computed tomography (CT) based volumetric assessment of RECIST (proposed as vRECIST) in locally advanced head and neck cancers (LAHNCs) undergoing treatment. MATERIAL AND METHODS: The pre-treatment SODs and CT estimated tumour volumes were recorded in 45 LAHNCs treated with radiotherapy (RT), chemoradiotherapy (CTRT) or thermochemoradiotherapy (HTCTRT). Tumour responses were assessed independently as per RECIST 1.1 and vRECIST by two radiation oncologists and grouped into complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). These response groups were evaluated for the likely congruence of the two approaches, as categorised independently by these two observers. RESULTS: All patients in stages III (n = 7), IVA (n = 16) and IVB (n = 22) were inoperable and had received either RT alone (n = 1), CTRT (n = 12) or HTCTRT (n = 32). Based on SODs criteria of RECIST 1.1, of the 45 patients, 5 and 40 were grouped as PR and SD by the first observer, while this changed to 34 and 10, respectively and 1 PD, with vRECIST (p < 0.001). Similarly, for the second observer, the 4 PR and 41 SD grouped using RECIST 1.1 were recategorised to 34 PR, 10 SD, and 1 PD by vRECIST (p < 0.001). Thus, a mismatch of 66.6% and 68.8%, respectively, was evident by observers first and second in categorising SD based on SODs of RECIST 1.1 vs PR on vRECIST. CONCLUSIONS: Treatment responses in LAHNCs assessed using SODs resulted in significant uncertainties and failed to reflect actual volumetric changes in tumours during treatment. It is perhaps time to consider replacing the SODs of RECIST 1.1 with vRECIST for unequivocal tumour response categorisation in the present era of image-based oncology practice.

Importance of glucose and its metabolism in neurodegenerative disorder, as well as the combination of multiple therapeutic strategies targeting α-synuclein and neuroprotection in the treatment of Parkinson's disease.

According to recent findings, Phosphoglycerate Kinase 1 (pgk-1) enzyme is linked to Parkinson's disease (PD). Mutations in the PGK-1 gene lead to decreases in the pgk-1 enzyme which causes an imbalance in the levels of energy demand and supply. An increase in glycolytic adenosine triphosphate (ATP) production would help alleviate energy deficiency and sustain the acute energetic need of neurons. Neurodegeneration is caused by an imbalance or reduction in ATP levels. Recent data suggest that medications that increase glycolysis and neuroprotection can be used to treat PD. The current study focuses on treatment options for disorders associated with the pgk-1 enzyme, GLP-1, and A2A receptor which can be utilized to treat PD. A combination of metformin and terazosin, exenatide and meclizine, istradefylline and salbutamol treatments may benefit parkinsonism. The review also looked at potential target-specific new techniques that might assist in satisfying unfulfilled requirements in the treatment of PD.

Mini review - The role of Glucocerebrosidase and Progranulin as possible targets in the treatment of Parkinson's disease.

As per recent reports, there is an association between glucocerebrosidase (Gcase) enzyme and Parkinson's disease (PD). In addition, certain mutations in the Gcase gene (GBA) and the progranulin (PGRN) gene are found to be linked with the imbalance in the levels of Gcase enzyme. This imbalance or decrease or impairment in Gcase activity can lead to Gaucher disease, frontotemporal lobar degeneration (FTLD), dementia, etc. Recent evidences suggest that the drugs used to treat these diseases can be used for PD. The present review has focused on the therapeutic approaches used for diseases linked with Gcase enzyme, which can be used for PD. The review also considered possible target specific novel strategies, which may help to meet the unmet needs in the treatment of PD.

Effect of Withania somnifera (L.) Dunal aqueous root extract on reinstatement using conditioned place preference and brain GABA and dopamine levels in alcohol dependent animals.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera (L.) Dunal (WS), a known'Rasayana' (rejuvenating agent) as per Ayurveda is prescribed to promote health, to increase longevity and to hasten recovery in disease convalescent stages. WS has demonstrated protective effect on alcohol dependence and withdrawal anxiety in previous experimental studies. AIM OF THE STUDY: To evaluate effect of WS on conditioned place behavioral paradigm (model of relapse) and on GABA and dopamine levels in critical brain areas in alcohol dependent animals. METHODOLOGY: Following Animal Ethics Committee permission, the mice (n = 24) were divided into the following study groups for experiment 1: 1 -distilled water (vehicle control), 2 -WS and 3 -Naltrexone. They were conditioned on conditioned place preference (CPP) using alcohol (2 gm/kg)/saline (1 ml) administered intraperitoneally for 8 days. WS and Naltrexone were administered during the period of extinction (6-8 days). Effect of WS (650 mg/kg) on reinstating behaviour of mice (time spent in alcohol paired compartment) primed with alcohol injection was noted. In experiment 2, effect of WS (450 mg/kg/) on GABA and dopamine levels in the midbrain, striatum and cortex (ng/gm) were measured in alcohol dependent rats (n = 24) following the first phase of standardisation assay (n = 36). The rats were made alcohol dependent for 15 days (intermittent access model) and WS was administered concurrently. GABA and dopamine levels were measured on Day 16. RESULTS: WS group showed decrease in time spent in alcohol paired compartment alike Naltrexone and it differed significantly compared to the distilled water control group (p < 0.05) Alcohol-dependent rats showed significant decrease in GABA and increase in dopamine levels vs distilled water in the midbrain, striatum and cortex. WS and Naltrexone administration showed rise in GABA and fall in dopamine in all the isolated brain parts in the respective groups (p < 0.05 vs alcohol treated group). CONCLUSION: Withania somnifera protected animals from relapse and showed beneficial effects on the brain neurotransmitters involved in alcohol dependence. The study provides substantial evidence for its potential application in alcohol use disorder.

The changing face of community-acquired methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of infection, both in hospitalised patients with significant healthcare exposure and in patients without healthcare risk factors. Community-acquired methicillin-resistant S. aureus (CA-MRSA) are known for their rapid community transmission and propensity to cause aggressive skin and soft tissue infections and community-acquired pneumonia. The distinction between the healthcare-associated (HA)-MRSA and CA-MRSA is gradually fading owing to the acquisition of multiple virulence factors and genetic elements. The movement of CA-MRSA strains into the nosocomial setting limits the utility of using clinical risk factors alone to designate community or HA status. Identification of unique genetic characteristics and genotyping are valuable tools for MRSA epidemiological studies. Although the optimum pharmacotherapy for CA-MRSA infections has not been determined, many CA-MRSA strains remain broadly susceptible to several non-ß-lactam antibacterial agents. This review aimed at illuminating the characteristic features of CA-MRSA, virulence factors, changing clinical settings and molecular epidemiology, insurgence into the hospital settings and therapy with drug resistance.

Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen.

The protein kinase C (PKC) signaling system plays a role in mood disorders and PKC inhibitors such as endoxifen may be an innovative medicine for bipolar disorder (BP) patients. In this study we show for the first time the antimanic properties of endoxifen in patients with bipolar I disorder (BPD I) with current manic or mixed episode. In a double-blind, active-controlled study, 84 subjects with BPD I were randomly assigned to receive endoxifen (4 mg/day or 8 mg/day) or divalproex in a 2:1 ratio. Patients orally administered 4 mg/day or 8 mg/day endoxifen showed significant improvement in mania assessed by the Young Mania Rating Scale as early as 4 days. The effect remained significant throughout the 21-day period. At study end point, response rates were 44.44% and 64.29% at 4 mg/day and 8 mg/day of endoxifen treatment, respectively. Thus, endoxifen has been shown as a promising novel antimanic or mood stabilizing agent.

Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era.

We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

Risk groups in children under six months of age using self-organizing maps.

Fetal and infant growth tends to follow irregular patterns and, particularly in developing countries, these patterns are greatly influenced by unfavorable living conditions and interactions with complications during pregnancy. The aim of this study was to identify groups of children with different risk profiles for growth development. The study sample comprised 496 girls and 508 boys under six months of age from 27 pediatric primary health care units in the city of Rio de Janeiro, Brazil. Data were obtained through interviews with the mothers and by reviewing each child's health card. An unsupervised learning, know as a self-organizing map (SOM) and a K-means algorithm were used for cluster analysis to identify groups of children. Four groups of infants were identified. The first (139) consisted of infants born exclusively by cesarean delivery, and their mothers were exclusively multiparous; the highest prevalences of prematurity and low birthweight, a high prevalence of exclusive breastfeeding and a low proportion of hospitalization were observed for this group. The second (247 infants) and the third (298 infants) groups had the best and worst perinatal and infant health indicators, respectively. The infants of the fourth group (318) were born heavier, had a low prevalence of exclusive breastfeeding, and had a higher rate of hospitalization. Using a SOM, it was possible to identify children with common features, although no differences between groups were found with respect to the adequacy of postnatal weight. Pregnant women and children with characteristics similar to those of group 3 require early intervention and more attention in public policy.

Trends in antimicrobial susceptibility of Salmonella Typhi from North India (2001-2012).

PURPOSE: Enteric fever is endemic in India with Salmonella Typhi being the major causative agent. Antibiotic therapy constitutes the mainstay of management. The present study was undertaken to find the susceptibility profile of Salmonella enterica var Typhi (S. Typhi) blood isolates in a tertiary care hospital between January 2001 and December 2012. MATERIALS AND METHODS: A retrospective analysis of laboratory records was carried out. Conventional blood culture method was used until 2009; from January 2010 onwards BACTEC 9240 system has been in use. Salmonella were confirmed by serotyping using group and type specific antisera. Antibiotic susceptibility was performed using the disk diffusion method. In addition 116 isolates were subjected to minimum inhibitory concentration testing for chloramphenicol, ciprofloxacin, amoxicillin and nalidixic acid (NA) using agar dilution and for ceftriaxone and azithromycin using E-strips (Biomerieux). RESULT: A total of 1016 typhoidal salmonellae were obtained. The predominant serotype obtained was S. Typhi (852, 83.8%) followed by Salmonella enterica var Paratyphi A (164, 16.2%). We observed a re-emergence of susceptibility to first line antibiotics and a notable decline in multidrug resistant (MDR) strains. We also found all recent isolates resistant to NA and susceptible to third generation cephalosporins and 84.5% of isolates having decreasing ciprofloxacin susceptibility using revised criteria as per Clinical and Laboratory Standards Institute 2012 guidelines. CONCLUSION: There has been re-emergence of susceptibility to first line antibiotics and a notable decline in MDR strains of S. Typhi. We have a very high resistance to NA and decreasing susceptibility to ciprofloxacin. Third generation cephalosporins and azithromycin seem to be effective therapeutic options. Judicious use of these antibiotics is mandatory to prevent emergence of resistant strains.

Epidemiological study of a large cluster of fungaemia cases due to Kodamaea ohmeri in an Indian tertiary care centre.

While performing molecular confirmation of phenotypically identified Candida tropicalis isolates, we re-identified a few isolates as Kodamaea ohmeri. This led us to the present epidemiological investigation of K. ohmeri fungaemia cases. All phenotypically identified C. tropicalis blood isolates during October 2008 through to December 2009 at our advanced paediatric centre were included for molecular identification by sequencing of the internal transcribed spacer and D1/D2 regions of rDNA. After identifying a large cluster K. ohmeri fungaemia cases, a case-control study was carried out retrospectively to analyse potential risk factors for K. ohmeri fungaemia. Molecular typing of the isolates was performed using a fluorescent amplified fragment length polymorphism (FAFLP) technique. The antifungal susceptibility testing was performed as per the M27-A3 protocol of CLSI. Thirty-eight (25.7%) of 148 phenotypically identified C. tropicalis isolates were confirmed as K. ohmeri by sequencing and FAFLP. By case-control analysis, piperacillin-tazobactam was significantly associated with the K. ohmeri fungaemia. The FAFLP analysis showed that all K. ohmeri isolates had >92% similarity. The azoles and echinocandins had good in vitro activity against K. ohmeri, though 86.8% of the isolates had MIC of 1 mg/L for amphotericin B. The response to antifungal therapy could be evaluated in 27 patients and 70.4% of patients recovered after antifungal therapy. The present study reports the largest cluster of K. ohmeri fungaemia from a single centre. The study also stresses the need for accurate identification of clinical yeast isolates.

A case of dual infection in a paediatric trauma victim of primary cutaneous aspergillosis caused by Aspergillus flavus and Aspergillus terreus.

Aspergillus spp. are widely distributed throughout the environment. They are opportunistic pathogens causing infection at various sites in the body such as lungs, sinuses, eyes, skin, central nervous system etc., Primary cutaneous aspergillosis is an uncommon disease entity. Primary infections usually occur at sites having disruption of the skin and usually occur in burn patients, trauma and surgical patients. A 4-year-old girl who was run over by a truck and suffered extensive de-gloving injury to bilateral lower limbs developed greenish discharge and scaly lesions around the wound margins after 50 days of hospital stay. The skin biopsy demonstrated the presence of thin septate hyphae branching at acute angles and culture demonstrated growth of Aspergillus flavus and Aspergillus terreus. The child was started on voriconazole therapy for 3 weeks and the lesion healed satisfactorily. Subsequent skin biopsy culture was negative for fungi. Prompt diagnosis and management of such cases can salvage the limbs in severe trauma cases.

Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects.

Endoxifen is an active metabolite of tamoxifen, a drug used in the treatment of breast cancer. In order to be clinically effective, tamoxifen must be converted to endoxifen by cytochrome P450 2D6 (CYP2D6). A study involving single escalating oral doses was conducted in humans to evaluate the safety, tolerability, and pharmacokinetics (PK) of endoxifen. This is the first study demonstrating that single oral doses of endoxifen are safe and well tolerated and have sufficient bioavailability to reach systemically effective levels in human subjects. Furthermore, it was found that endoxifen is rapidly absorbed and systemically available and that it displays dose proportionality in peak drug concentrations in plasma (C(max)) and area under the concentration-time curve extrapolated from 0 to ∞ (AUC(0-∞)) over the dose range 0.5-4.0 mg.

Salivary nickel and chromium in patients with fixed orthodontic appliances.

The purpose of this study was to determine the alterations in the chromium and nickel concentrations in the saliva of orthodontic patients treated with fixed orthodontic appliances. Forty-five orthodontic patients were included in this study. The first group consisted of 15 patients (7 female, 8 male) with fixed appliances placed in their upper and lower arches. The second group consisted of 15 patients (8 female, 7 male) with a fixed appliance placed only in the upper arch. The control group consisted of 15 patients (7 female, 8 male) who were not undergoing orthodontic treatment. Four samples of stimulated saliva were collected from each patient before insertion of the fixed appliance, 1 week after insertion of the appliance, 1 month after insertion of the appliance, and 2 months after insertion of the appliance. The same 4 samples of saliva were collected from each control patient at the same time intervals as for the fixed-appliance groups. The chemical analyses were done with an electrothermal atomic absorption spectrophotometer (Perkin Elmer 2380, Perkin Elmer Corp, Baden Seewerk, Germany). The Wilcoxon matched-pairs signed ranks test was used to test differences between samples before and after insertion of orthodontic appliances. A Kruskal Wallis 1-way analysis of variance was used to test differences in nickel and chromium concentration among the 3 test groups. It was observed that there was a large variation in the concentrations of both nickel and chromium in saliva. No significant differences were found between the no-appliance group and the samples obtained after insertion of the appliances. The results of the study suggest that fixed orthodontic appliances do not significantly affect nickel and chromium concentrations of saliva during the first 2 months of treatment.

Picrorhiza kurroa (Kutaki) Royle ex Benth as a hepatoprotective agent--experimental & clinical studies.

Picrorhiza kurroa (Pk), a known hepatoprotective plant, was studied in experimental and clinical situtations. The standardization of active principles--Picroside 1 and 2 was done with High Performance Liquid Chromatography. Picroside 1 ranged from 2.72 to 2.88 mg/capsule and picroside 2 from 5.50 to 6.00 mg/capsule. In the galactosamine-induced liver injury in rats, Pk at a dose of 200 mg/kg p.o. showed a significant reduction (p < 0.05) in liver lipid content, GOT and GPT. In a randomised, double-blind placebo controlled trial in patients diagnosed to have acute viral hepatitis (HBsAg negative), Pk root powder 375 mg three times a day was given for 2 weeks (n = 15) or a matching placebo (n = 18) was given. Difference in values of bilirubin, SGOT and SGPT was significant between placebo and Pk groups. The time in days required for total serum bilirubin to drop to average value of 2.5 mg% was 75.9 days in placebo as against 27.44 days in Pk group. The present study has shown a biological plausability of efficacy of Pk as supported by clinical trial in viral hepatitis, hepatoprotection in animal model and an approach for standardizing extracts based on picroside content.

Mutagenicity testing of nine herbicides and pesticides currently used in agriculture.

Nine herbicides and pesticides were tested for their mutagenicity using the Drosophila sex-linked recessive lethal mutation assay. These are Ambush, Treflan, Blazer, Roundup, 2,4-D Amine, Crossbow, Galecron, Pramitol, and Pondmaster. All of these are in wide use at present. Unlike adult feeding and injection assays, the larvae were allowed to grow in medium with the test chemical, thereby providing long and chronic exposure to the sensitive and dividing diploid cells, i.e., mitotically active spermatogonia and sensitive spermatocytes. All chemicals induced significant numbers of mutations in at least one of the cell types tested. Some of these compounds were found to be negative in earlier studies. An explanation for the difference in results is provided. It is probable that different germ cell stages and treatment regimens are suitable for different types of chemicals. larval treatment may still be valuable and can complement adult treatment in environmental mutagen testing.

Induction of delayed mutations by benzene and ethylene dibromide in Drosophila.

Two carcinogens, ethylene dibromide and benzene, were used to induce delayed (germinal mosaic) sex-linked recessive lethal mutations in spermatozoa and spermatids of adult Drosophila males. Significant numbers of delayed mutations (in F3) were scored in absence of conventional (in F2) mutations. A large proportion of nonlethal F2 cultures carried delayed mutations, so much so that, in some cultures, all F2 females were carriers of mutations. The mechanism through which single strand damage to treated X chromosomes can result in such delayed lethals is discussed. These observations indicate that the delayed mutation test should be used for testing the mutagenicity of environmental compounds, especially carcinogens, which tested negative in the conventional sex-linked recessive lethal mutation test. The data will support the relationship between mutagenesis and carcinogenesis and, also will further enhance the sensitivity of the Drosophila mutation assay.

Frameshift mutations in Salmonella induced by the extracts of medicinal herbs Lannea edulis (Sond.) Engl. and Monotes glaber Sprague.

Lannea edulis and Monotes glaber have been prescribed for various affectations in the traditional medical practice of Zimbabwe and other parts of Africa. Mutagenicity testing using Salmonella typhimurium strains TA97a, TA98, and TA100, indicated that the aqueous extracts of these plants induced frameshift mutations in Salmonella. The extract of L. edulis displayed marginal mutagenicity in strain TA97a while that of M. glaber showed a significant dose-dependent mutagenicity in both strains TA97a and TA98. There was no mutagenic effect observed in strain TA100. Two other plant extracts, those of Lannea discolor and Dolichos kilimandscharicus, were nonmutagenic in all three strains.